Most protein conformational disorders have both sporadic and inherited forms. Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are unique in that they also have infectious origins. The TSE infectious agent is a self-propagating pathological isoform of the prion protein, PrP. Proteins involved in various other neurodegenerative diseases form similar self-propagating amyloid structures, but only recently have some of those protein aggregates been hypothesized to be potentially infectious. The infectious origin of TSEs relies upon transmission and propagation of the prion protein in its aggregation-prone conformation. Although the infectious mechanism and fundamental pathology is conserved in TSEs of different species, cross-species transmission can be very inefficient. The defining factors of this prion species barrier are unknown but are likely related to the capacity of prion proteins to propagate in different conformations (prion strains). In this pilot project make use of a yeast prion model system that does not rely on the development of clinical disease to assess prion transmissibility and the propensity for replication. We will address two important questions that will enhance our understanding of the prion strains and the differences between infectious and non-infectious amyloid 1) What makes an amyloid structure infectious or non-infectious? 2) What controls species barriers that limit infection and prion transmissibility? We are in a position to address these questions in a unique manner based on the systems that we have developed and the results we have obtained thus far. This pilot project will allow us to begin to utilize our system for structural work and develop and characterize a similar system for PrP.